The long-term objective of this research is to study bone ingrowth into synthetic biodegradable osteoinductive scaffolds for reconstruction of craniofacial defects. Since bone morphogenetic proteins (BMPs) signaling is highly regulated, the graft has to be loaded with doses of 4-5 orders of magnitude (with adverse side effects) higher than the amount found endogenously. An attractive alternative is to use peptides, based on the active domains of BMPs to initiate the cascade of osteogenesis. The strategy involves covalent attachment of an osteoinductive azide-functionalized "BMP peptide", corresponding to amino acid residues 73-92 of the recombinant human bone morphogenetic protein-2 (rhBMP-2), to a novel bioresorbable poly(lactide-co-glycolide fumarate) (PLGF) scaffold. The short lactide-co-glycolide chains in PLGF impart degradability to the macromer while the fumarate units provide sites for crosslinking for structural support. We hypothesized that the crosslinked scaffold provides structural support to the regenerating region and induces osteogenesis by the interaction of migrating bone marrow stromal (BMS) cells with the grafted BMP peptide. Moreover, the scaffold will degrade concurrent with the production of mineralized matrix to increase bone volume. The aim of this proposal is to determine osteoinductivity and the extent of bone formation of BMP peptide grafted PLGF scaffold in-vitro and in-vivo. In the first part of Aim 1, the effect of PLGF composition and scaffold porosity on degradation characteristics and mechanical strength will be determined. The outcome of Aim 1.1 is the best lactide: glycolide ratio of PLGF and best porosity of the scaffold. In the second part of Aim 1, effect of BMP peptide grafted PLGF on differentiation and mineralization of BMS cells will be determined in-vitro. The outcome of Aim 1.2, is the best density of BMP peptide grafted to PLGF scaffold, as judged by the highest mineral content. In Aim 2, we will determine the effect of BMP peptide grafted scaffold on bone formation in critical-size rat cranial defect in-vivo. Experimental groups will include scaffolds grafted with mutant BMP peptide (negative control), BMP peptide (experimental group), and scaffolds with rhBMP-2 protein (positive control). Success will be judged by the continuous bridging of new bone across the scaffold and by bone mineral density. PUBLIC HEALTH RELEVANCE: Over twenty million people in USA are totally edentulous and about half a million children worldwide are born annually with congenital craniofacial deformities. Degradable biomaterials that are space occupying, osteoinductive, have the consistency to protect the defect from soft tissue collapse, and degrade concurrent with the formation of new extra-cellular matrix to increase bone volume have the potential for breakthroughs in the development of adaptable scaffolds to the changing craniofacial defect.